Glutethimide (

brand name A brand is a name, term, design, symbol or any other feature that distinguishes one seller's goods or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create and ...

s included Doriden, Elrodorm, and Noxyrom) is a central nervous system (CNS)

depressant Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various ...

drug of the

piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...

chemical class Chemical classification systems attempt to classify elements or compounds according to certain chemical functional or structural properties. Whereas the structural properties are largely intrinsic, functional properties and the derived classi ...

, one of many non-barbiturate, "barbiturate-like"

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter gamma-aminobutyric acid (GABA). For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic ...

medications exhibiting general calming, relaxing, or "tranquilizing" properties in addition to relieving anxiety and promoting sleep. As such, "nerve pills" or "sleeping pills" were common vernacular descriptions of these types of medications

History

Glutethimide was developed

Ciba Specialty Chemicals Ciba was a chemical company based in and near Basel, Switzerland. "Ciba" stood for "Chemische Industrie Basel" (Chemical Industries Basel) and was formed when the non-pharmaceuticals elements of Novartis were spun out in 1997, following the merg ...

in 1954, and

approved Approved may refer to: *Approved drug, a preparation that has been validated for a therapeutic use by a ruling authority of a government *''Approved'', a 2013 album by Chester Thompson Chester Thompson (born December 11, 1948) is an American dr ...

for medical use in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

by the U.S.

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in 1957. It was indicated for treating

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, and branded Doriden by Ciba. Generic trade names that followed included Elrodorm and Noxyrom. Following the passage of the

Controlled Substances Act of 1970 The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

in the U.S., followed by the creation of the U.S. Drug Enforcement Agency (DEA) in 1973, the " War on Drugs" began to prioritize the criminalization of

combination drugs A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. F ...

containing

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

s. The DEA declared glutethimide to be as habit-forming and addicting as barbiturates and other highly-regulated CNS depressants such as

Quaalude Methaqualone is a hypnotic sedative. It was sold under the brand names Quaalude ( ) and Sopor among others, which contained 300 mg of methaqualone, and sold as a combination drug under the brand name Mandrax, which contained 250 mg me ...

and

Placidyl Ethchlorvynol is a GABA-ergic hypnotic sedative medication first developed by Pfizer in the 1950s. In the United States, it was sold by Abbott Laboratories under the trade name Placidyl. Placidyl was available in 200 mg, 500 mg, and 7 ...

. Abrupt cessation of this substance can result in rebound effects similar to those in withdrawal from any

substance, including

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

s and

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

Chemical composition and synthesis

The (R) isomer has a faster

onset of action Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other meth ...

and more potent

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

activity in animal models than the (S) isomer. Glutethimide synthesis

The base catalyzed conjugate addition of 2-phenylbutyronitrile 69-68-6(1) to

ethyl acrylate Ethyl acrylate is an organic compound with the formula CH2CHCO2CH2CH3. It is the ethyl ester of acrylic acid. It is a colourless liquid with a characteristic acrid odor. It is mainly produced for paints, textiles, and non-woven fibers. It is ...

(2) gives ethyl 4-cyano-4-phenylhexanoate
CID:139890735
(3). Alkaline hydrolysis of the nitrile group into an amide group, and subsequent acidic cyclization of the product affords the desired glutethimide (4).

Mechanism of action and uses

Glutethimide is a

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

enzyme inducer, enabling the body to convert higher amounts of

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

, frequently leading to ingestion of glutethimide alongside codeine-containing products, such as Tylenol No. 3 or No. 4, and widespread misuse, overdose, and fatalities. Colloquially called "hits," "pancakes and syrup," or "Dors and 4s", this combination is highly potent and often lethal due to extreme

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

. In recreational quantities, any form of glutethimide was colloquially called a "Ciba" and all

trade name A trade name, trading name, or business name is a pseudonym used by companies that do not operate under their registered company name. The term for this type of alternative name is fictitious business name. Registering the fictitious name with ...

s of the medicine were manufactured as a white pill/tablet with a score line directed to be taken by mouth, and containing 500mg of the

active ingredient An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. ...

. During the 1980s, glutethimide became increasingly harder to access and subject to many restrictions as a CSA-classified Schedule II substance, but market demand for the product constinued to exist among northeastern U.S. states and metropolitan centers, leading to the substance's clandestine "underground" manufacturing and sale, which only increased when

methaqualone Methaqualone is a hypnotic sedative. It was sold under the brand names Quaalude ( ) and Sopor among others, which contained 300 mg of methaqualone, and sold as a combination drug under the brand name Mandrax, which contained 250 mg me ...

was fully withdrawan from the U.S. market and classified a

Schedule I drug The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

Clinical research

Glutethimide's effect on quickening the conversion of codeine to morphine was studied clinically, including some research in the 1970s in various countries. In these studies, it was used under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, particularly as a ''Substitutionmittel'' that may be a useful alternative to

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

. Glutethimide was available in the United States until 1993, when production ceased and it was withdrawn from the market. Since 2013, the U.S.

DEA The Drug Enforcement Administration (DEA) is a United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit drug trafficking and distribution within the U.S. It is the lead agency for domes ...

has limited annual production to three grams, equivalent to six Doriden tablets, suggesting that current use is limited to small-scale research.

Legal status

United States

Glutethimide is a Schedule II drug under the

Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...

. It was originally a Schedule III drug in the United States under the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

, but in 1991 it was upgraded to Schedule II, several years after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination. It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g.

References

{{GABAA receptor positive allosteric modulators Abandoned drugs CYP2D6 inducers Sedatives Piperidines Glutarimides GABAA receptor positive allosteric modulators